PROJECT SUMMARY (See instructions); Decreased VWF levels or defects in VWF function cause von Willebrand disease (VWD) the most common inherited bleeding disorder. The reduced plasma survival of VWF is a novel mechanism causing type 1 VWD (type IC) and may represent 10-15% of type 1 VWD cases. While our studies have defined the characteristic elements of the type IC phenotype, very little is known about the mechanisms governing VWF clearance under normal or pathological conditions. Our goal is to define VWF clearance mechanisms. We have identified many novel mutations in the VWF coding region for VWD patients. These novel sequence variations are distributed throughout all domains within the VWF protein. Our previous expression studies revealed that type 2A VWD results from a complex intersection of mechanisms: defective secretion, multimerization, regulated storage, or ADAMTSI 3 susceptibility. The 2A mutations, when co-expressed with wild-type VWF, appeared to negatively impact at least one mechanism important for normal VWF processing. While decreased secretion and reduced plasma survival have been implicated as mechanisms causing type 1 VWD, the impact of type 1 mutations on multimerization, regulated storage/secretion, and ADAMTSI 3-mediated degradation is not well-defined. We will define the mechanisms causing type 1 VWD and develop a model that would allow one to predict the impact of mutations on VWD phenotype. ADAMTSI 3-mediated proteolysis of VWF clearly plays a crucial role in type 2A VWD. Some studies have suggested that ADAMTSI 3 may also contribute to the type 1 VWD phenotype. A percentage of ADAMTSI 3 is reported to bind to circulating VWF and thus may be cleared quickly in type IC VWD patients. We will determine if type 1 VWF variants have increased susceptibility to ADAMTS-13 proteolysis and examine if ADAMTSI3 levels are reduced in type IC VWD. The knowledge gained from these studies will increase our understanding of mechanisms causing VWD, leading to the development of more effective treatment strategies